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Journal of Virology, November 2003, p. 11616-11624, Vol. 77, No. 21
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.21.11616-11624.2003

Changes in Mumps Virus Gene Sequence Associated with Variability in Neurovirulent Phenotype

Steven A. Rubin,^1* Georgios Amexis,¹ Mikhail Pletnikov,² Jacqueline Vanderzanden,¹ Jeremy Mauldin,¹ Christian Sauder,¹ Tahir Malik,¹ Konstantin Chumakov,¹ and Kathryn M. Carbone^1,2

DVP/Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892,¹ Departments of Psychiatry and Medicine, Johns Hopkins University, Baltimore, Maryland 21205²

Received 11 April 2003/ Accepted 16 June 2003

Mumps virus is highly neurotropic and, prior to widespread vaccination programs, was the major cause of viral meningitis in the United States. Nonetheless, the genetic basis of mumps virus neurotropism and neurovirulence was until recently not understood, largely due to the lack of an animal model. Here, nonneurovirulent (Jeryl Lynn vaccine) and highly neurovirulent (88-1961 wild type) mumps virus strains were passaged in human neural cells or in chicken fibroblast cells with the goal of neuroadapting or neuroattenuating the viruses, respectively. When tested in our rat neurovirulence assay against the respective parental strains, a Jeryl Lynn virus variant with an enhanced propensity for replication (neurotropism) and damage (neurovirulence) in the brain and an 88-1961 wild-type virus variant with decreased neurotropic and neurovirulent properties were recovered. To determine the molecular basis for the observed differences in neurovirulence and neuroattenuation, the complete genomes of the parental strains and their variants were fully sequenced. A comparison at the nucleotide level associated three amino acid changes with enhanced neurovirulence of the neuroadapted vaccine strain: one each in the nucleoprotein, matrix protein, and polymerase and three amino acid changes with reduced neurovirulence of the neuroattenuated wild-type strain: one each in the fusion protein, hemagglutinin-neuraminidase protein, and polymerase. The potential role of these amino acid changes in neurotropism, neurovirulence, and neuroattenuation is discussed.

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* Corresponding author. Mailing address: DVP/OVRR/CBER/FDA, Building 29A, Room 1A-21, 8800 Rockville Pike, Bethesda, MD 20892. Phone (301) 827-1974. Fax (301) 480-5679. E-mail: rubins{at}cber.fda.gov.

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Journal of Virology, November 2003, p. 11616-11624, Vol. 77, No. 21
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.21.11616-11624.2003

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